Currently there are more than 5 million people living with Alzheimer's disease (AD) in the United States and this number is projected to nearly triple by 2050 with annual costs of long term care expected to exceed $1 trillion. Alzheimer's disease (AD) is the most common form of dementia among the elderly, resulting from progressive memory loss associated with the aberrant accumulation of amyloid-beta (A) in the brain and cerebrovasculature over the course of multiple decades. While genetic evidence clearly implicates the A pathway in Alzheimer's disease, ?-secretase and -secretase inhibitors appear to have on-target toxicities and A immunotherapies have not demonstrated clinical efficacy in phase 3 human trials. OrPhi's approach acts upstream of the immunotherapies by preventing the formation of toxic A oligomers inside neurons without altering normal A processing and function. OrPhi Therapeutics has demonstrated proof of concept in a novel A oligomer Alzheimer's disease model (APPE693Q) using a pharmacological chaperone (OT1001) designed to decrease ganglioside-bound A. Pharmacological chaperone OT1001 has good drug-like properties, including good potency, high target selectivity, low cytotoxicity, and good oral bioavailability and plasma PK characteristics. Blood-brain-barrier (BBB) penetration is acceptable; however there is an opportunity for enhancement of BBB penetration providing a means to lower the effective dose of our candidate molecule. This grant application proposes a rationally designed, highly focused medicinal chemistry effort followed by in vitro and in vivo assessment of various pharmacological properties. These assessments include in vitro target binding affinity, selectivity, cell-based enhancement properties, general cell toxicit, metabolic stability, cardiotoxicity, genotoxicity, BBB penetration, brain PK and oral bioavailability. Quantitative criteria have been established for culling OT1001 and OT1001 analogues. At the conclusion of the project, OT1001 and non-culled analogues will be ranked according to lowest predicted effective dose and a lead candidate will be selected.